The present invention provides for aminoaryl oxazolidinone N-oxide compounds. These compounds are exceedingly water soluble which is useful in preparing pharmaceutical formulations of these compounds. They are also rapidly converted back to the parent amines in vivo, making them useful as prodrugs of the parent amines.
These compounds have antibiotic activity comparable to the parent amines. They are effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms, such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp., and in organisms such as Mycoplasma spp.
A variety of antibiotic oxazolidinone compounds are known in the art. For example, please see the following:
WO 95/07271, published Mar. 16, 1995, xe2x80x9cSubstituted Oxazine and Thiazine Oxazolidinones Antimicrobialsxe2x80x9d; WO96/15130, published May 23, 1996, xe2x80x9cBicyclic Oxazine and Thiazine Oxazolidinone Antibacterialsxe2x80x9d; WO96/13502, published May 9, 1996, xe2x80x9cPhenyloxazolidinone Antimicrobialsxe2x80x9d; WO 93/23384, published Nov. 25, 1993, xe2x80x9cOxazolidinone Antimicrobials Containing Substituted Diazine Moietiesxe2x80x9d; WO 90/02744, published Mar. 22, 1990; U.S. Pat. No. 5,164,510; U.S. Pat. No. 5,225,565; U.S. Pat. No. 5,182,403; xe2x80x9c5xe2x80x2-Indolinyl-5xcex2-Amidomethyloxazolidin-2-onesxe2x80x9d; WO 95/25106, published Sep. 21, 1995, xe2x80x9cOxazolidinone Derivatives and Pharmaceutical Compositions Containing Themxe2x80x9d; WO 93/09103, published May 13, 1993, xe2x80x9cSubstituted Aryl and Heteroaryl-Phenyloxazolidinonesxe2x80x9d; WO 95/14684, published Jun. 1, 1995, xe2x80x9cEsters of Substituted Hydroxyacetyl-Piperazine Phenyl Oxazolidinonesxe2x80x9d; PCT/US96/05202, filed Apr. 18, 1996, xe2x80x9cSpirocyclic and Bicyclic Diazinyl and Carbazinyl Oxazolidinonesxe2x80x9d; U.S. Pat. Nos. 5,231,188 and 5,247,090, xe2x80x9cTricyclic [6,6,5]-Fused Oxazolidinone Antibacterial Agents;xe2x80x9d WO 96/23788, published Aug. 8, 1996, xe2x80x9cHetero-Aromatic Ring Substituted Phenyloxazolidinone Antimicrobials;xe2x80x9d and WO 94/13649, published Jun. 23, 1994, xe2x80x9cTropone-Substituted Phenyloxazolidinone Antibacterial Agents.xe2x80x9d
Nowhere do these patents, applications or publications teach or suggest N-oxide oxazolidinone compounds.
U.S. Pat. No. 4,722,928 discloses N-oxide prodrug derivatives of 3-hydroxy morphinans and partial morphinans analgesics, agonist-antagonists, and narcotic antagonists, which are useful therapeutic entities providing enhanced bioavailability of these compounds from orally administered dosage forms. In contrast, there is no change in the bioavailability of the N-oxide compounds of the present invention.
This patent further states that there is no way to accurately predict which prodrug structure will be suitable for a particular drug. A derivative which may work well for one drug may not do so for another. Differences in the absorption, metabolism, distribution, and excretion among drugs do not permit generalizations to be made about prodrug design.
Chemical Abstracts 118:147331y (1993) discloses anti-cancer anthracene amine N-oxide prodrugs with low cytotoxicity which are bioreduced within anaerobic neoplastic tissue to the cytotoxic amine anticancer agents. There is no suggestion that N-oxide prodrugs can be bioreduced in normal tissue. These compounds are also potentially useful against anaerobic bacterial and protozoal infections.
L. H. Patterson, xe2x80x9cRationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent,xe2x80x9d Cancer and Metastasis Review 12:119-134 (1993) discloses that such N-oxides are not intrinsically cytotoxic. It further states that investigations into the fate of N-oxide administration to animals show that, in general, aliphatic N-oxides are stable in vivo and are recovered quantitatively following intravenous dosing. Hence, the article concludes that it would appear that aliphatic N-oxides are not metabolised in oxygenated tissue to any significant extent. In contrast, the aliphatic N-oxide compounds of the present invention are surprisingly and unexpectedly reduced back to the parent amine very rapidly in vivo.
The problem in the art is difficulty in formulating the parent amine compounds for intravenous and injectable use. The N-oxide compounds of the present invention have high water solubility and are readily formulated in aqueous vehicles.
The present invention particularly provides:
A compound of the formula I 
wherein X1 and X2 are independently
xe2x80x94H,
xe2x80x94F, or
xe2x80x94Cl;
wherein Q1 is: 
wherein Z1 is
a) xe2x80x94CH2xe2x80x94, or
b) xe2x80x94CH(R5)xe2x80x94CH2xe2x80x94;
wherein Z2 is
a) xe2x80x94O2Sxe2x80x94,
b) xe2x80x94Oxe2x80x94, or
c) xe2x80x94N(R8)xe2x80x94;
wherein Z3 is
a) xe2x80x94O2Sxe2x80x94, or
b) xe2x80x94Oxe2x80x94;
wherein A1 is
a) Hxe2x80x94, or
b) CH3xe2x80x94;
wherein A2 is
a) Hxe2x80x94,
b) HOxe2x80x94,
c) CH3CO2xe2x80x94,
d) CH3xe2x80x94,
e) CH3Oxe2x80x94,
f) R2Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94,
g) R3Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
h) R4xe2x80x94C(O)xe2x80x94NHxe2x80x94,
i) (C1-C2)alkylxe2x80x94Oxe2x80x94C(O)xe2x80x94, or
j) HOxe2x80x94CH2xe2x80x94; or
A1 and A2 taken together are: 
or
b) Oxe2x95x90
wherein R1 is
a) xe2x80x94CHO,
b) xe2x80x94COCH3,
c) xe2x80x94COCHCl2,
d) xe2x80x94COCHF2,
e) xe2x80x94CO2CH3,
f) xe2x80x94SO2CH3, or
g) xe2x80x94COCH2OH;
wherein R2 is
a) Hxe2x80x94,
b) CH3xe2x80x94,
c) phenyl-CH2-, or
d) CH3C(O)xe2x80x94;
wherein R3 is
a) (C1-C3)alkyl-, or
b) phenyl-;
wherein R4 is
a) Hxe2x80x94,
b) (C1-C4)alkyl,
c) aryl-(CH2)p,
d) ClH2Cxe2x80x94,
e) Cl2HCxe2x80x94,
f) FH2Cxe2x80x94,
g) F2HCxe2x80x94, or
h) (C3-C6)cycloalkyl;
wherein R5 is
a) Hxe2x80x94, or
b) (C1-C3)alkyl;
wherein R6 is
a) Hxe2x80x94, or
b) HOH2Cxe2x80x94;
wherein R7 is
a) Hxe2x80x94, or
b) H3Cxe2x80x94;
wherein R8 is
a) R2Oxe2x80x94C(R10)(R11)xe2x80x94C(O)xe2x80x94,
b) R3Oxe2x80x94C(O)xe2x80x94,
c) R4xe2x80x94C(O)xe2x80x94, 
f) H3Cxe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94,
g) R9xe2x80x94SO2xe2x80x94, 
i) R12xe2x80x94NHxe2x80x94C(O)xe2x80x94;
wherein R9 is
a) xe2x80x94CH3,
b) xe2x80x94CH2Cl
c) xe2x80x94CH2CHxe2x95x90CH2,
d) aryl, or
e) xe2x80x94CH2CN;
wherein R10 and R11 are independently
a) Hxe2x80x94,
b) CH3xe2x80x94; or
R10 and R11 taken together are xe2x80x94CH2xe2x80x94CH2xe2x80x94;
wherein R12 is xe2x80x94(CH2)p-aryl;
wherein R13 is
a) R2Oxe2x80x94C(R10)(R11)xe2x80x94C(O)xe2x80x94,
b) R3Oxe2x80x94C(O)xe2x80x94,
c) R4xe2x80x94C(O)xe2x80x94,
d) R9xe2x80x94SO2xe2x80x94, or
e) R12xe2x80x94NHxe2x80x94C(O)xe2x80x94;
wherein m is zero (0) or one (1);
wherein n is one (1) to three (3), inclusive;
wherein p is zero (0) or one (1);
wherein aryl is phenyl substituted with zero (0) or one (1) of the following:
a) xe2x80x94F,
b) xe2x80x94Cl,
c) xe2x80x94OCH3,
d) xe2x80x94OH,
e) xe2x80x94NH2,
f) xe2x80x94(C1-C4)alkyl,
g) xe2x80x94Oxe2x80x94C(O)xe2x80x94OCH3,
h) xe2x80x94NO2, or
i) xe2x80x94CN;
with the following provisos:
1) in the moiety of formula II, Z1 is xe2x80x94CH(R5)xe2x80x94CH2xe2x80x94wherein R5 is (C1-C3)alkyl, only when n is one (1), Al is H and A2 is R2Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, R3Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, or R4xe2x80x94C(O)xe2x80x94NHxe2x80x94; and
2) in the moiety of formula II, when Z1 is xe2x80x94CH2xe2x80x94, n is one (1).
The present invention more particularly provides:
The compound of claim 1 wherein Q1 is the moiety of formula II;
The compound of claim 1 wherein Q1 is the moiety of formula III;
The compound of claim 1 wherein Q1 is the moiety of formula IV;
The compound of claim 1 wherein Q1 is the moiety of formula V;
The compound of claim 1 wherein one of X1 and X2 is xe2x80x94H and the other is xe2x80x94F or wherein X1 is xe2x80x94F and X2 is xe2x80x94F; and
The compound of claim 1 wherein R1 is acetyl.
The compounds of the present invention are named according to the IUPAC or CAS nomenclature system.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-Cj indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, (C1-C3)alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight and branched forms thereof.
Throughout this application, abbreviations which are well known to one of ordinary skill in the art may be used, such as xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, and xe2x80x9cEtxe2x80x9d for ethyl.
The following Charts I-IX describe the preparation of the parent amine compounds, which are the starting compounds from which the N-oxide compounds of the present invention are prepared. All of the starting compounds are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. The following applications and publications which further describe and exemplify these procedures are hereby incorporated by reference herein: WO 95/07271, published Mar. 16, 1995; WO96/15130, published May 23, 1996; WO 95/25106, published Sep. 21, 1995; WO96/13502, published May 9, 1996; WO 93/23384, published Nov. 25, 1993; WO 95/4684, published Jun. 1, 1995; and PCT/US96/05202, filed Apr. 18, 1996.
In the text below corresponding to these charts, the formula at the left margin corresponds to a specific Q2 moiety in the charts and the other variables are as defined with X1 and X2 most often being hydrogen or fluorine and R1 most often being xe2x80x94COCH3, for purposes of example only.
I-A Using the procedures from WO 95/07271, published Mar. 16, 1995, page 21, line 33, thru page 23, line 32 for preparation of the intermediate sulfide and then oxidation to the sulfone using the general procedures from WO 95/07271, published Mar. 16, 1995, page 15, line 32 thru page 16, line 14.
I-B Using the procedures described in WO 95/07271, published Mar. 16, 1995, page 21, line 33, thru page 23, line 32, but substituting oxazolidine for thiazolidine.
II-A Using the general procedures from WO 95/07271, published Mar. 16, 1995, page 12, line 31, thru page 16, line 14.
II-B Using the general procedures from WO 95/07271, published Mar. 16, 1995, page 12, line 31 thru page 16, line 14, but substituting 2-methylthiomorpholine for thiomorpholine. 2-Methylthiomorpholine is prepared according to the procedure of Gallego, et al, J. Org. Chem., 1993, 58, 3905-11.
II-C Using the general procedures from WO96/15130, published May 23, 1996, Examples 2 and 3 at page 14, line 24, thru page 17, line 21.
III-A Using the general procedures from WO 95/07271, published Mar. 16, 1995, page 19, line 6, thru page 21, line 13; and page 23, line 33, thru page 24, line 35.
III-B Using the general procedures from WO96/15130, published May 23, 1996, Example 1 at page 12, line 1, thru page 14, line 22.
IV-A Using the general procedures from WO 95/25106, published Sep. 21, 1995, page 20, line 27 thru page 22, line 5 but substituting azetidine for piperidine.
IV-B Using the general procedures of WO96/13502, published May 9, 1996, Example 11 at page 53, line 32 through page 56, line 3, but substituting 1-(diphenylmethyl)-3-azetidinone in place of 1-benzyl-3-pyrrolidinone. 1-(Diphenylmethyl)-3-azetidinone can be prepared by the procedure of Chatterjee, et al, Synthesis, 1973, 153-4.
IV-C From IV-B using the general procedure from WO96/13502, published May 9, 1996, page 56, line 4 through line 17.
IV-D From IV-C using the general procedure from WO 95/25106, published Sep. 21, 1995, page 28, line 26 through page 29, line 5.
IV-E Using the general procedures from WO96/13502, published May 9, 1996, Example 2 at page 33, line 4, thru page 36, line 22.
IV-F Starting with IV-E, and using procedures well known for acetylation; e.g., acetic anhydride and triethylamine in a suitable solvent.
IV-G Using the general procedures from WO96/13502, published May 9, 1996, Example 7 at page 43, line 36, thru page 47, line 28.
IV-H Using the general procedures from WO96/13502, published May 9, 1996, Example 6 at page 40, line 31, thru page 43, line 34.
IV-I Using the procedures of WO96/13502, published May 9, 1996, Example 1 at page 29, line 25 thru page 33, line 2.
IV-J Wherein R2 is H; using the procedure described in WO96/13502, published May 9, 1996, Examples 12 and 13 at page 56, line 19 thru page 59, line 4, but substituting 3-acetylaminoazetidine hydrochloride in place of 3-(trifluoro-acetylamino)pyrrolidine hydrochloride. 3-Acetylaminoazetidine hydrochloride is prepared by the procedure of Nisato, et al., J. Heterocycl. Chem. 1985, 22, 961-3.
IV-J Wherein R2 is methyl; using the procedure described in WO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56 line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of 3-(trifluoroacetylamino)pyrrolidine hydrochloride and substituting methoxyacetyl chloride in place of benzyloxyacetyl chloride.
IV-J Wherein R2 is benzyl; using the procedure described in WO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56 line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of 3-(trifluoroacetylamino)pyrrolidine hydrochloride.
IV-J Wherein R2 is acetyl; using the procedure described in WO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56 line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of 3-(trifluoroacetylamino)pyrrolidine hydrochloride and substituting acetoxyacetyl chloride in place of benzyloxyacetyl chloride.
IV-K Wherein R3 is methyl, ethyl, propyl, or phenyl; using the procedure described in WO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56 line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of 3-(trifluoroacetyl-amino)pyrrolidine hydrochloride and substituting methyl, ethyl, propyl, or phenyl chloroformate in place of benzyloxyacetyl chloride.
IV-L Wherein R4 is hydrogen; using the procedure described in WO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56 line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of 3-(trifluoroacetylamino)pyrrolidine hydrochloride and substituting methyl formate in place of benzyloxyacetyl chloride.
IV-L Wherein R4 is all others listed; using the procedure described in WO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56 line 19 thru page 59 line 27, but substituting 3-acetylarninoazetidine hydrochloride in place of 3-(trifluoroacetylamino)pyrrolidine hydrochloride and substituting the appropriate acid chloride in place of benzyloxyacetyl chloride.
IV-M Using the general procedures of WO96/13502, published May 9, 1996, Example 1, Steps 2 thru 7, at page 30, line 14 thru page 33, line 2, but substituting methyl N-benzylazetidine-3-carboxylate in place of 1-(diphenyl-methyl)-3-methoxyazetidine. Methyl N-benzylazetidine-3-carboxylate can be prepared by the procedure of Mason, et al, EP 169602 A1.
IV-N Starting with IV-M and using the general procedures of WO 95/25106, published Sep. 21, 1995, page 22, line 11 through line 20.
V-A Using the procedure from WO 95/25106, published Sep. 21, 1995, page 20, Example 1, but using-pyrrolidine instead of piperidine.
V-B Using the procedures of WO96/13502, published May 9, 1996, Example 11 at page 53, line 32, thru page 56, line 3.
V-C From V-B, following the procedure of WO96/13502, published May 9, 1996, page 56, lines 4 through 17.
V-D From V-C, using the general procedure of WO 95/25106, published Sep. 21, 1995, page 28, line 26, thru page 29, line 5.
V-E Using the procedures described in WO96/13502, published May 9, 1996, Example 10 at page 50, line 25, thru page 53, line 30. Or, from V-C by reduction using methods well known in the art such as sodium borohydride in methanol.
V-F From V-E using standard acetylation procedures; e.g., acetic anhydride in pyridine.
V-G As described in WO96/13502, published May 9, 1996, Example 7 at page 43, line 36, thru page 47, line 28 but substituting 1-benzyl-3-methyl-3-pyrrolidinol hydrochloride for 1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride. 1-Benzyl-3-methyl-3-pyrrolidinol hydrochloride can be prepared from 1-benzyl-3-pyrrolidinone by methods known in the art, eg, reaction with methylmagnesium bromide and treatment of the product with one equivalent of hydrochloric acid. 1-Benzyl-3-pyrrolidinone is commercially available.
V-H Using the general procedures of WO96/13502, published May 9, 1996, Example 6 at page 40, line 31 through page 43, line 34, but substituting 1-benzyl-3-methyl-3-pyrrolidinol hydrochloride (prepared as described above) in place of 1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride.
V-I As described in WO96/13502, published May 9, 1996, Example 1 at page 29, line 25, thru page 33, line 2, but substituting commercially available 1-benzyl-3-pyrrolidinol for 1-(diphenylmethyl)-3-azetidinol.
V-J Wherein R2 is H and R5 is H; using the procedure described in WO96/13502, published May 9, 1996, Examples 12 and 13 at page 56, line 19, thru page 59, line 4;
V-J Wherein R2 is methyl and R5 is H; using the procedure described in WO96/13502, published May 9, 1996, Example 12 at page 56, line 19 thru page 58, line 27 but substituting methoxyacetyl chloride for benzyloxyacetyl chloride.
V-J Wherein R2 is benzyl and R5 is H; using the procedure described in WO96/13502, published May 9, 1996, Example 12 at page 56, line 19 thru page 58, line 27.
V-J Wherein R2 is acetyl and R5 is H; using the procedure described in WO96/13502, published May 9, 1996, Example 12 at page 56, line 19 thru page 58, line 27 but substituting acetoxyacetyl chloride for benzyloxyacetyl chloride.
V-J Where R2 is H and R5 is methyl; using the procedures described in WO96/13502, published May 9, 1996, Example 15 at page 62, lines 5-28.
V-J Wherein R2 is benzyl and R5 is methyl; using the procedures described in WO96/13502, published May 9, 1996, Example 15, Step 1, at page 62, lines 5-19.
V-J Wherein R2 is methyl or acetyl and R5 is methyl; using the procedures described in WO96/13502, published May 9, 1996, Example 15, Step 1, at page 62, lines 5-19, but substituting methoxyacetyl chloride or acetoxyacetyl chloride for benzyloxyacetyl chloride.
V-J Wherein R5 is other alkyl; using the general procedures described above but subsituting other 4-alkyl-3-aminopyrrolidines in place of 3-amino-4-methylpyrrolidine.
V-K Wherein R3 is methyl, ethyl, propyl or phenyl and R5 is H; using the procedure described in WO96/13502, published May 9, 1996, Example 12 at page 56, line 19 thru page 58, line 27 but substituting methyl chloroformate, ethyl choroformate, propylchloroformate, or phenylchloroformate for benzyloxyacetyl chloride.
V-K Wherein R3 is methyl, ethyl, propyl, or phenyl and R5 is methyl; by reaction of (S)-(N)-[[[3-fluoro-4-(3-amino-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide with the appropriate chloroformate. The above amine is prepared according to the procedures of WO96/13502, published May 9, 1996, Example 14, Steps 1-8, at page 59, line 6 through page 61, line 29.
V-K Wherein R5 is other alkyl; From the appropriate amine and chloroformate.
The amine is prepared according to the procedures of WO96/13502, published May 9, 1996, Example 14, Steps 1-8, at page 59, line 6 through page 61, line 29, but starting with other 3-alkyl-4-aminopyrrolidines in place of 4-amino-3-methylpyrrolidine.
V-L Where R4 is H and R5 is H; using the procedure described in WO96/13502, published May 9, 1996, Example 12 at page 56, line 19 thru page 58, line 27 but substituting methyl formate in place of benzyloxyacetyl chloride.
V-L Where R4 is all others listed and R5 is H; using the procedure described in WO96/13502, published May 9, 1996, Example 12 at page 56, line 19 thru page 58, line 27 but substituting the appropriate acid chloride in place of benzyloxyacetyl chloride.
V-L Where R4 is H and R5 is methyl; by reaction of formic acid and dicyclohexylcarbodiimide. The required amine is prepared according to the procedures of WO96/13502, published May 9, 1996, Example 14, Steps 1-8, at page 59, line 6 through page 61, line 29.
V-L Where R4 is all others and R5 is methyl; by reaction of (S)-(N)-[[[3-fluoro-4-(3-amino-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide with the appropriate acid chloride. The required amine is prepared according to the procedures of WO96/13502, published May 9, 1996, Example 14, Steps 1-8, at page 59, line 6 through page 61, line 29.
V-L Where R5 is other alkyl; Using the above procedures, but starting with other 3-alkyl-4-aminopyrrolidines in place of 4-amino-3-methylpyrrolidine.
V-M Using the general procedure from WO 95/25106, published Sep. 21, 1995, page 22, lines 6 through 12, 5, but using pyrrolidine-3-carboxylic acid methyl ester instead of piperidine-4-carboxylic acid ethyl ester. Pyrrolidine-3-carboxylic acid methyl ester is prepared by the procedure of Morgans, et al, Tetrahedron Lett., 1979, 1959.
V-N From V-M, using the general procedure of WO 95/25106, published Sep. 21, 1995, page 22, lines 12 through 20.
VI-A Using the general procedures from WO 95/25106, published Sep. 21, 1995, page 20, line 27, thru page 22, line 5.
VI-B Using the procedure of WO 95/25106, published Sep. 21, 1995, WO 95/25106, published Sep. 21, 1995, page 22, line 21 thru line 26.
VI-C From VI-B, using the procedure from WO 95/25106, published Sep. 21, 1995, page 22, lines 27 through 35.
VI-D From VI-C, using the procedure from WO 95/25106, published Sep. 21, 1995, page 28, line 26 thru page 29, line 5.
VI-E Prepared from VI-C by reduction via standard procedures known in the art; eg, sodium borohydride in methanol.
VI-F Prepared from VI-E by procedures known in the art; eg, acetic anhydride and triethylamine.
VI-G Using the procedures from WO96/13502, published May 9, 1996, Example 7, page 43, line 36 thru page 47, line 28 but substituting commercially available 4-hydroxy-4-methylpiperidine for 3-hydroxy-3-methylazetidine.
VI-H Using the procedures from WO 95/25106, published Sep. 21, 1995, page 20, line 27 thru page 22, line 5, but substituting 4-methoxy-4-methylpiperidine in place of piperidine. 4-Methoxy-4-methylpiperidine can be prepared according to the procedure of McManus, et al, J. Med. Chem., 1965, 8, 766-776.
VI-I Using the procedures from WO 95/25106, published Sep. 21, 1995, page 20 line 27 thru page 22, line 5, but substituting 4-methoxypiperidine for piperidine. 4-Methoxypiperidine can be made by the procedure of McManus, et al, J. Med. Chem., 1965, 8, 766-776.
VI-J Wherein R2=H; Prepared by reaction of (S)-N-[[3-[4-(4-aminopiperidinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (prepared according to the procedures of WO 95/25106, published Sep. 21, 1995, page 22, line 36 thru page 23, line 24) with acetoxyacetyl chloride and triethylamine followed by hydrolysis of the acetoxy group with methanolic potassium carbonate.
VI-J Wherein R2=methyl; prepared by reaction of the starting material of VI-J (R2=H) with methoxyacetyl chloride and triethylamine.
VI-J Wherein R2 is benzyl; prepared by reaction of the starting material of VI-J (R2=H) with benzyloxyacetyl chloride and triethylamine.
VI-J Wherein R2 is acetyl; prepared by reaction of the starting material of VI-J (R2=H) with acetoxyacetyl chloride and triethylamine.
VI-K Wherein R3 is methyl, ethyl, propyl, or phenyl; prepared by reaction of the starting material of VI-J (R2=H) with methyl-, ethyl-, propyl-, or phenylchloroformate.
VI-L Wherein R4=H; By reaction of the starting material of VI-J (R2=H) with methylformate.
VI-L Wherein R4=all others listed; By reaction of the starting material of VI-J (R2=H) with the appropriate acid chloride.
VI-M Using the procedure from WO 95/25106, published Sep. 21, 1995, page 22, line 6 thru line 12.
VI-N Using the procedure from WO 95/25106, published Sep. 21, 1995, page 22, lines 12 through 20.
VII-A Using the general procedures of WO 95/25106, published Sep. 21, 1995, page 20, line 27 through page 22, line 5, but substituting commercially available azepine in place of piperidine.
VII-B Using the procedure of WO 95/25106, published Sep. 21, 1995, page 22, line 21 thru line 26 but substituting 1,4-dioxo-8-aza-spiro[4.6]undecane for 1,4-dioxo-8-aza-spiro[4.5]decane. 1,4-Dioxo-8-aza-spiro[4.6]undecane can be prepared by the procedure of R. A. Johnson, et al, J. Org. Chem., 1968, 33, 3187-3195.
VII-C From VII-B, following the procedure of WO96/13502, published May 9, 1996, page 56, lines 4 through 17.
VII-D From VII-C using the general procedure of WO 95/25106, published Sep. 21, 1995, page 28, line 26, thru page 29, line 5.
VII-E Prepared from VII-C by reduction via standard procedures known in the art;
eg, sodium borohydride in methanol.
VII-F Prepared from VII-E by procedures known in the art; eg, acetic anhydride and triethylamine.
VII-G Using the procedures from WO96/13502, published May 9, 1996, Example 7, page 43, line 36 thru page 47, line 28 but substituting 4-hydroxy-4-methyl-azepine for 3-hydroxy-3-methylazetidine. 4-Hydroxy-4-methylazepine can be prepared by the procedure pf Grob, et al, Helv. Chim.Acta, 1962, 45, 1823-1830.
VII-H Using the general procedures of WO96/13502, published May 9, 1996, Example 6, page 40, line 31 through page 43, line 34, but substituting 1-benzyl-4-methyl-4-azepinol in place of 1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride. 1-Benzyl-4-methyl-4-azepinol can be prepared by the reaction of methyl magnesium bromide with 1-benzyl-4-azepinone. 1-Benzyl-4-azepinone can be prepared by the procedure of Casy, et al, J. Chem. Soc. 1964, 5130-5132.
VII-I As described in WO96/13502, published May 9, 1996, Example 1, at page 29, line 25, thru page 33, line 2, but substituting 1-benzyl-4-azepinol for 1-(diphenylmethyl)-3-azetidinol. 1-Benzyl-4-azepinol can be prepared by the procedure of S. Sakanoue, et al, Chem. Pharm. Bull., 1990 38, 2981-2985.
VII-J Wherein R2 is H; using the procedure described in WO96/13502, published May 9, 1996, Examples 12 and 13, page 56, line 19, thru page 59, line 4 but substituting 4-(trifluoroacetylamino)azepine in place of 3-(trifluoroacetylamino)pyrrolidine. 4-(Trifluoroacetylamino)azepine can be prepared by reaction of 1-benzyl-4-azepinamine with trifluoroacetic anhydride in a suitable solvent such as chloroform, followed by removal of the benzyl protecting group via hydrogenolysis using palladium on carbon as a catalyst in a solvent such as ethyl acetate. 1-Benzyl-4-azepinamine can be prepared by the procedure of Morosawa, et al, Bull. Chem. Soc. Jpn., 1958, 31, 418-422.
VII-J Wherein R2 is methyl; using the procedure described in WO96/13502, published May 9, 1996, Example 12, page 56, line 19 through page 58, line 27, but substituting 4-(trifluoroacetylamino)azepine for 4-(trifluoroacetylamino)pyrrolidine and substituting methoxyacetyl chloride in place of benzyloxyacetyl chloride.
VII-J Wherein R2 is benzyl; using the procedure described in WO96/13502, published May 9, 1996, Example 12, page 56, line 19 through page 58, line 27, but substituting 4-(trifluoroacetylamino)azepine for 4-(trifluoroacetyl-amino)pyrrolidine.
VII-J Wherein R2 is acetyl; using the procedure described in WO96/13502, published May 9, 1996, Example 12, page 56, line 19 through page 58, line 27, but substituting 4-(trifluoroacetylamino)azepine for 4-(trifluoroacetyl-amino)pyrrolidine and substituting acetoxyacetyl chloride in place of benzyloxyacetyl chloride.
VII-K Wherein R3 is methyl, ethyl, propyl, or phenyl; prepared by reaction of (S)-N-[[3-[4-(4-aminoazepinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (prepared as an intermediate in the synthesis of VII-J) with the appropriate chloroformate and triethylamine in chloroform.
VII-L Wherein R4 is H; Prepared by reaction of (S)-N-[[3-[4-(4-aminoazepinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (prepared as an intermediate in the synthesis of VII-J) with formic acid according to the general procedure of WO 93/23384, published Nov. 25, 1993, page 23, lines 4-17.
VII-L Wherein R4 is all others; Prepared by reaction of (S)-N-[[3-[4-(4-aminoazepinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (prepared as an intermediate in the synthesis of VII-J) with the appropriate acid chloride and triethylamine.
VIII-M Using the procedure from WO 95/25106, published Sep. 21, 1995, page 22, line 6 thru line 12, but substituting azepine-4-carboxylic acid ethyl ester in place of piperidine-4-carboxylic acid ethyl ester. Azepine-4-carboxylic acid ethyl ester can be prepared from azepine-4-carboxylic acid by normal procedures known in the art, eg, reaction with ethanol and hydrochloric acid. Azepine-4-carboxylic acid can be prepared by the procedure of Krogsgaard-Larsen, et al, Eur. J. Med. Chem. Chim. Ther., 1979, 14, 157-164.
VII-N From VII-M, using the general procedure of WO 95125106, published Sep. 21, 1995, page 22, lines 12 through 20.
VIII-A Wherein R2=H; According to the procedure of WO 95/14684, published Jun. 1, 1995, page 9, lines 1-28.
VIII-A Wherein R2=methyl; According to the general procedures of WO 93/23384, published Nov. 25, 1993, page 19, lines 26-33.
VIII-A Wherein R2=benzyl; According to the procedure of WO 95/14684, published Jun. 1, 1995, page 9, lines 1-14.
III-A Wherein R2=acetyl; According to the procedure of WO 95/14684, published Jun. 1, 1995, page 28, lines 24-35.
VIII-B Wherein R3=Me, Et, Pr, or Ph; Using the general procedure from WO 93/23384, published Nov. 25, 1993, page 23, lines 19-28 and substituting methyl-, ethyl, propyl, or phenylchloroformate as appropriate.
VIII-C Wherein R4=H; Using the general procedures from WO 93/23384, published Nov. 25, 1993, page 23, lines 4-17.
VIII-C Wherein R4=all others; Using the general procedures from WO 93/23384, published Nov. 25, 1993, page 23, lines 19-28, and substituting the appropriate acid chloride for methylchloroformate.
VIII-D Prepared according to the general procedure found in WO 93/23384, published Nov. 25, 1993, page 25, lines 13-25.
VIII-E Prepared according to the general procedure from WO 93/23384, published Nov. 25, 1993, page 25, lines 13-25, but substituting commercially available 5-oxo-2-tetrahydrofurancarboxylic acid in place of (R)-2-tetrahydrofuranoic acid.
VIII-F Prepared according to the procedure of WO 93/23384, published Nov. 25, 1993, page 18, lines 10-17.
VIII-G Prepared from N-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and the appropriate sulfonyl chloride using the general procedure from WO 93/23384, published Nov. 25, 1993, page 23, lines 19-28. Methyl, chloromethyl, allyl, and substituted arylsulfonyl chlorides are commercially available. Cyanomethylsulfonyl chloride can be prepared according to the procedure of M. P. Sammes, et al, J. Chem. Soc. (C)., 1971, 2151-2155.
VIII-H Prepared from N-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and piperonyl chloride using the general procedure from WO 93/23384, published Nov. 25, 1993, page 23, lines 19-28. Piperonyl chloride is commercially available.
VIII-I Prepared from N-[[3-[4-[3-fluoro4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and the appropriate carboxylic acid using the general procedure of WO 95/14684, published Jun. 1, 1995, page 10, lines 4-17. The acids are commercially available.
VIII-J Prepared from N-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and the appropriate isocyanate. The required isocyanates are commercially available.
IX-A Wherein R2 is H; Prepared according to the procedures of PCT/US96/05202, filed Apr. 18, 1996, Examples 1, 2 and 3, page 12, line 11 through page 15, line 7.
IX-A Wherein R2 is methyl; Prepared according to the general procedures of PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14, lines 16-32, but substituting methoxyacetyl chloride for benzyloxyacetyl chloride.
IX-A Wherein R2 is benzyl; Prepared accroding to the procedures of PCT/US96/05202, filed Apr. 18, 1996. Example 2, page 14, lines 16-32.
IX-A Wherein R2 is acetyl; Prepared according to the general procedures of PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14, lines 16-32, but substituting acetoxyacetyl chloride for benzyloxyacetyl chloride.
IX-B Using the general procedure of PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14, lines 16-32, but substituting the appropriate chloroformate for benzyloxyacetyl chloride.
IX-C Wherein R4 is H; Prepared from (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]-octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (PCT/US96/05202, filed Apr. 18, 1996, page 14, lines 21-24) using the general procedures from WO 93/23384, published Nov. 25, 1993, page 23, lines 4-16.
IX-C Wherein R4 is all others listed; Using the general procedure of PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14, lines 16-32, but substituting the appropriate acid chloride in place of benzyloxyacetyl chloride.
IX-D Using the general procedure of PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14, lines 16-32, but substituting the appropriate sulfonyl chloride in place of benzyloxyacetyl chloride. The sulfonyl chlorides can be obtained as described for VIII-G.
IX-E Prepared from (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (PCT/US96/05202, filed Apr. 18, 1996, page 14, lines 21-24) and the appropriate carboxylic acid using the general procedures of WO 93/23384, published Nov. 25, 1993, page 18, lines 10-17. The appropriate carboxylic acids are commercially available.
IX-F Prepared by combining (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (PCT/US96/05202, filed Apr. 18, 1996, page 14, lines 21-24) and the appropriate isocyanate.
The required isocyanates are commercially available.
The compounds of this invention are prepared by oxidation of a suitable precursor amine with any of a variety of oxidizing agents. Suitable oxidants include pertrifluoroacetic acid, meta-chloroperbenzoic acid (MCPBA), and magnesium monoperoxyphthalate (MMPP). For example, the synthesis is shown below for the case wherein Q1 is morpholine and the oxidant is MMPP. 
Oxidation of any of the oxazolidinones of Charts I-IX in which Q2 is any of the other groups previously described is carried out similarly.
Charts X-XVIII show the final N-oxide compounds of the present invention which are prepared from the parent amines of Charts I-IX, respectively, by using the above General Procedures.
It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry.
The compounds of the present invention have an advantage over the parent amines in being exceedingly water soluble (see Table 1 below). For example, the compound of Example No. 2 has a solubility of 409 mg/ml. The parent amine has a water solubility of only 3.7 mg/ml. The N-oxide compounds of the present invention also retain all the in vitro and in vivo activities of the parent amines. The enhanced water solubility makes the N-oxide compounds of the present invention ideal for intravenous or injectable formulations
Procedure for Measuring Solubility:
In all solubility studies, an excess of compound is added to 0.5 to 1 ml of pH 7, 50 mM phosphate buffer or other vehicle of interest. The samples are capped and stirred via magnetic stir bars for 24 to 48 hours at room temperature. Samples are filter centrifuged (800xc3x97g) for 5-10 minutes through Millipore Ultrafree-MC 0.22 micron filter units. The supernate is analyzed by either UV or HPLC to quantitate the drug concentration. Results of the solubility testing of the compounds of the present invention are given above in Table 1.
The oxazolidinone compounds of the present invention have useful activity against a variety of microorganisms. The in vitro activity of compounds of the present invention are assessed by standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in xe2x80x9cMethods for Dilution Antimicrobial Susceptiblity Tests for Bacteria That Grow Aerobicallyxe2x80x9d (MFT) published January 1993 by the National Committee for Clinical Laboratory Standards (NCCLS), 771 East Lancaster Avenue, Villanova, Pa. 19084, USA. The activity of selected compounds of the present invention against Staphylococcus aureus and Streptococcus pneumoniae are shown in Table 2.
As such, the compounds of the present invention are useful for treating microbial infections in humans or other warm-blooded animals by administering to a patient in need thereof an effective amount of a compound of Formula I. The compound is administered in a pharmaceutical composition orally, parenterally (such as subcutaneously or intravenously), or topically. Preferably the compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day, more preferably, from about 3.0 to about 50 mg/kg of body weight/day.
The following compounds of the present invention (with cross-references to the formulas in the charts below) are preferred: